Both amphetamine (AMPH) and cocaine (COC) addicts develop binge patterns in which the drug is frequently administered over prolonged periods of time, producing a nearly continuous intake regimen. For both drugs, during these runs dysphoria and paranoia progressively increase. Similarly, both AMPH and COC, when administered continuously to animals, induce clear stages of behavior, with initial exploratory and stereotypy phases and the eventual development of a "late-stage" characterized by hallucinogen-like behaviors. Yet the two drugs have been found to be quite dissimilar many of the persisting effects on brain they produce when delivered continuously'. Continuous AMPH has a selective neurotoxic effect on caudate dopamine terminals, whereas COC does not, and continuous COC induces persisting alterations in cholinergic and GABA receptors, especially in caudate, whereas AMPH does not. In recent studies of degeneration patterns following continuous AMPH and COC administration we have discovered that both drugs similarly induce highly specific degeneration of axons in the lateral habenula (LH) and fasciculus retroflexus (FR). We now propose to further study this phenomenon in detail. We will further characterize pattern and extent of degeneration, determine the doses and duration of drugs necessary to induce it, and attempt to clarify the neurotransmitters of the degenerating axons and the location of their cell bodies. Using lesioning techniques, receptor blockers, and direct agonists we will attempt to determine what neural pathways and neurotransmitters mediate this effect. In behavioral studies, we will attempt to determine persisting effects of these degenerated axons and whether surgical transections of the principal pathways involved alter the sequence of behaviors observed following continuous COC, especially during repeated binges similar to those in the very chronic addict. Microdialysis techniques will be used to test, in caudate, the important hypothesis that FR axons which degenerate mediate part of the negative feedback circuitry regulating dopamine release. This will be done by measuring in drug-naive and animals pretreated with COC pellets the levels of dopamine and GABA induced by doses of the Dl agonist SKF38393. In secondary experiments we will also further study the pronounced degeneration in hippocampus and parahippocampus which we have recently found following continuous administration of phencyclidine, which is a second and important drug model of psychosis. This laboratory is in a unique position to conduct these studies because of our expertise in slowrelease drug pellets, degeneration patterns, and behavior.